Project Summary: It is likely that there are several immunogenetic forms of IBD, with CD and UC representing the broadest clinical classifications. While therapeutic options have increased over the past decade, our ability to target newer biologic therapies to specific subgroups of patients has lagged behind. Our recent studies have shown that CD patients with elevated GM-CSF auto-antibodies (GM-CSF Ab) are at high risk for progressive disease requiring surgery, and that neutrophil antimicrobial functions are reduced in this subset of patients. We hypothesize that: 1) elevated GM-CSF Ab will predict increased risk for complicated disease and surgery; 2) GM-CSF Ab level is a familial trait; and 3) GM-CSF Ab suppress neutrophil function by inhibiting GM-CSF bioactivity. We will test these hypotheses in the following Aims: Aim 1. Validate GM- CSF Ab antibody prediction of CD behavior. The serum concentration of neutralizing GM-CSF Ab will be determined in a prospective cohort of CD patients and related to disease behavior. These data will determine whether neutralizing GM-CSF Ab increase risk for complicated CD behavior requiring surgery, relative to current serologic markers and therapies. Aim 2. Determine the heritability of serum GM-CSF Ab levels. The serum concentration of GM-CSF Ab will be determined in affected and unaffected first degree relatives of index CD patients and the intra-class correlation coefficient and estimate of familial aggregation for GM-CSF Ab will be determined. These data will determine whether neutralizing GM-CSF Ab are inherited as a quantitative trait influenced by CARD15 and IRGM genetic polymorphisms. Aim 3. Examine GM-CSF Ab regulation of neutrophil function. The serum concentration of GM-CSF Ab will be determined and related to basal and GM-CSF dependent neutrophil STAT3/5 activation, cell survival, and antimicrobial functions including CD11B activation, adhesion, phagocytosis, microbial killing, and oxidative burst. These data will determine whether GM-CSF Ab suppress neutrophil STAT5 activation and antimicrobial function, while promoting STAT3 activation and cell survival.